Renin is a proteolytic enzyme produced and secreted into the bloodstream by the juxtaglomerular cells of the kidney. In the bloodstream, renin cleaves a peptide bond in the serum protein angiotensinogen to produce a decapeptide known as angiotensin I. A second enzyme known as angiotensin converting enzyme, cleaves angiotensin II. Angiotensin II is a potent pressor agent responsible for vasoconstriction and elevation of cardiovascular pressure. Attempts have been made to control hypertension by blocking the action of renin or by blocking the formation of angiotensin II in the body with inhibitors of angiotensin I converting enzyme.
Many classes of compounds have been described as inhibitors of the action of renin or angiotensinogen. Renin inhibitors of most interest are high potency, orally-active compounds having a low-cost method of synthesis.
Several families of renin inhibitor compounds have been described which possess the medicinally-significant properties of high potency and therapeutically-effective oral bioavailability. These families of peptide mimetic renin inhibitors are characterized by the presence of a propargyl moiety attached to glycyl residue within the backbone of the peptide mimetic structure. Other families of peptide mimetic compounds are characterized by the presence of an allyl moiety attached to a glycyl residue within the peptide mimetic backbone.
Renin inhibitors containing propargyl glycyl or allyl glycyl residues are described in published patent documents. For example, EP Appl. #186,977 published 9 Jul. 1986 describes renin-inhibiting compounds containing an alkynyl moiety, specifically a propargyl glycine moiety, attached to the main chain between the N-terminus and the C-terminus, such as N-[4(S)-[(N)-[bis(1-naphthylmethyl)acetyl]-D,L-propargylglycylamino]-3(S)- hydroxy-6-methylheptanoyl]-L-isoleucinol. U.S. Pat. No. 5,212,185 issued 18 May 1993 describes piperidinyl-terminated alkylamino ethynyl alanine amino diol compounds as renin inhibitors. U.S. Pat. No. 5,223,535 issued 29 Jun. 1993 describes propargyl glycine amino propargyl diol compounds as renin inhibitors. U.S. Pat. No. 5,227,401 issued 13 Jul. 1993 describes alkylamino--alkylamino-terminated ethynyl alanine amino diol compounds as renin inhibitors. U.S. Pat. No. 5,246,969 issued 21 Sep. 1993 describes di-propargyl-containing aryl-alkylsulfonyl-terminated amino diol compounds as renin inhibitors. U.S. Pat. No. 5,252,591 issued 12 Oct. 1993 describes pyridinyl/quinolinyl-terminated alkylamino ethynyl alanine amino diol compounds as renin inhibitors. PCT Application WO 94/04508 published 3 Mar. 1994 describes imidazolyl/benzimadazolyl-terminated alkylamino ethynyl alanine amino diol compounds as renin inhibitors. PCT Application WO 94/04518 published 3 Mar. 1994 describes morpholino-thiomorpholino-terminated alkylamino ethynyl alanine amino diol compounds as renin inhibitors. PCT Application WO 94/04536 published 3 Mar. 1994 describes ethynyl alanine amino diol compounds having a piperazinyl-terminated group or a piperazinyl-alkylamino-terminated group as renin inhibitors.
There are many conventional methods known for making protected amino acids which can be used as intermediates in synthesis of a wide variety of peptides and peptide mimetics [W. N. Speckamp et al, J. Org. Chem., 58, 3259-3268 (1993)]. For example, amidoalkylation of C-nucleophiles with glycine cation equivalents has been used to make protected .alpha.-substituted glycine derivatives [P. Munster et al, Synthesis, 223-225 (1987)]. Also, certain .gamma.,.delta. unsaturated N-protected .alpha.-amino acid methyl esters have been made by coupling allylsilanes with glycine cation equivalents in the presence of a Lewis acid catalyst, but which method when used to react propynyltrimethylsilane with glycidyl cation equivalent gave an unusable Diels-Alder adduct [H. H. Mooiweer et al, Tetrahedron, 45, 4627-4636 (1989)]. Many of these methods are inappropriate for making N-protected .alpha.-substituted amino acids because such processes frequently require the presence of a Lewis acid to which certain amino acid protecting groups are sensitive.
All of the earlier-mentioned propargyl-glycine or ethynyl-alanine-containing renin inhibitors are characterized by multi-step synthetic routes involving expensive or hard-to-make intermediates. In particular, these multi-step synthetic routes require the use of a stereo-specific N-protected .alpha.-substituted amino acid key intermediate, namely, Boc-protected L-propargylglycine, which is not readily available at low cost from commercial sources. Some methods are known for making this key intermediate. For example, one earlier method involves alkylation of diethylacetamidomalonate with propargyl bromide followed by multi-step manipulations to obtain chiral N-Boc-L-propargylglycine [O. Leukart et al, Helv. Chem. Acta., 59, 2181-2183 (1976)]. In U.S. Pat. No. 5,212,185 published 18 May 1993, there is described a reaction of L-propargylglycine with di-tert-butyl-dicarbonate in the presence of potassium carbonate to make Boc-protected L-propargylglycine intermediate. Because of these complicated multi-step syntheses and the high cost of this L-propargylglycine intermediate, there has been delay in the commercial development of propargylglycine-containing renin inhibitors.
Thus, there remains need for new synthetic routes for making low cost N-protected .alpha.-substituted amino acids which can be used in peptide synthesis, particularly for making medicinal products such as renin inhibitors.